How an international research funder's forum developed guiding principles to ensure value and reduce waste in research.

Background: When health-related research funding agencies choose to fund research, they balance a number of competing issues: costs, stakeholder views and potential benefits. The REWARD Alliance, and the related Lancet-REWARD Campaign, question whether those decisions are yielding all the value they could. Methods: A group of health-related research funding agencies, organisations that represent health-related research funding agencies and those that inform and set health-related-research funding policy from around the world have come together since 2016 to share, learn, collaborate and influence emerging practice. This group meets under the name of the Ensuring Value in Research Funders' Forum (EViR Funders' Forum). The EViR Funders' Forum worked together to develop a set of ten Guiding Principles, that if funders adhered to would reduce research waste and ensure value in research. Results: The EViR Funders' Forum has previously agreed and published a Consensus Statement. The Forum has agreed on a set of ten Guiding Principles to help health-research funders to maximise the value of research by ensuring that: research priorities are justifiable; the design, conduct and analysis of research minimise bias; regulation and management are proportionate to risks; methods and findings are accessible in full; and findings are appropriately and effectively disseminated and used. Conclusions: When setting research funding policy, we must balance multiple stakeholders' needs and expectations. When funders do this well, they maximise the probability of benefits to society from the research they support - when funders do this badly, they passively allow or actively contribute to research waste. These challenges must be resolved by funders either working together or in conjunction with other actors in the research ecosystem.

Examining the role of funders in ensuring value and reducing waste in research: An organizational case-study of the Patient-Centered Outcomes Research Institute.

International experts have recommended actions that funders can take to improve the value of research investments. They state that self-assessment and public sharing are the basis for accountability and improvement. We examined our policies and practice to determine the extent to which the Patient-Centered Outcomes Research Institute's (PCORI) policies and practices as a research funder align with international best practice recommendations. A self-audit of current policies and practice against 17 recommendations and 35 sub-recommendations representing five major stages of research production, based on adapted methods used for self-assessment by another funder, was performed.  Fit of existing PCORI policies and practices with 35 sub-recommendations, qualitative assessment of adequacy (area of strength; area of partial strength; area of growth; not applicable) for 17 recommendations for five stages of research production was assessed. Of the 17 recommendations, 15 were applicable to PCORI's research mission and focus.  PCORI has policies and practices in place for all elements of six recommendations ("area of strength") and policies that address each element but with some still in active development for three ("area of partial strength"). PCORI is partially addressing six of the 15 relevant recommendations ("area of growth"). Areas for growth include making study protocols publicly available, improving policies on data sharing, and enhancing collaboration with other funders to reduce redundant funding. A voluntary consortium of international funders is underway to encourage further progress, including additional self-assessment and public sharing for accountability. These findings indicate PCORI has undertaken efforts to align its funding practices with international recommendations to ensure the value of public dollars invested in research.  Further efforts will likely require additional coordination and collaboration between funders and stakeholders.

Noncommercial US Funders' Policies on Trial Registration, Access to Summary Results, and Individual Patient Data Availability.

Importance: Incomplete information about existing research is an underlying cause of research waste. National and international initiatives and requirements have been launched to address this issue. Objectives: To characterize current clinical trial transparency policies among the largest noncommercial US funders and examine whether the policies are concordant with international funders. Design, Setting, and Participants: This retrospective review of public information used methods developed for documenting funder policies internationally; 2 researchers searched each funder's website and Google between May and November 2018 to locate trial transparency policies for 10 top US funders. Key informants at each funding organization were contacted by email and given 3 or more weeks to review and confirm or correct the findings. Nonresponders were contacted 2 or more additional times. Descriptive statistics were calculated to summarize the findings. The study was conducted using publicly available policy information with findings confirmed by funder representatives where possible. Participants included top 10 noncommercial US health research funders with the highest reported investment in health research (2013 dollars) who fund clinical trials. Data analysis was conducted from November 6, 2018, to November 23, 2018. Exposures: Availability of policies addressing each of the 3 key trial transparency domains as specified by the World Health Organization in 2017. Main Outcomes and Measures: Independent assessment by 2 investigators of availability (yes or no) of a policy addressing registration for trials, sharing of summary results, and individual participant data sharing activities; requirements (yes, no, or supportive statement) of these policies in terms of completeness, timeliness, public access, and provision of additional technical or financial support to meet data sharing requirements; description (yes or no) of internal monitoring for policy adherence. Results: All 10 funders acknowledged the outreach. One funder who indicated that less than 1% of their research funding goes to clinical trials was removed. Six (67%) of the remaining 9 top US funders have a publicly available written policy for all 3 major trial transparency domains. The most comprehensive trial transparency practice among US funders addresses summary results sharing as follows: 8 of 9 US funders (89%) have a policy, 5 of 9 US funders (56%) require reporting of summary results within 1 year, and 6 of 9 US funders (67%) monitor compliance with their summary results sharing policy. For clinical trial registration, 7 of 9 US funders (78%) have a policy and 5 of 9 US funders (56%) require registration and monitor trial registration to measure adherence to the policy. Conclusions and Relevance: In this study, overall the proportion of US funders with policies and practices to support trial transparency in this sample was similar or compared favorably with the larger international sample of noncommercial funders recently reported.

A Patient-Centered Approach to Comparative Effectiveness Research Focused on Older Adults: Lessons From the Patient-Centered Outcomes Research Institute.

The mission of the Patient-Centered Outcomes Research Institute (PCORI) is to fund the production of high-quality evidence that will enable patients and clinicians to make informed, personalized healthcare decisions. Since 2012, the PCORI has invested $177 million in patient-centered comparative effectiveness research (CER) that specifically targets the health needs of older adults, with additional relevant studies in its broader portfolio. Developing the PCORI's research portfolio has provided us with significant insights into what factors to consider when conducting CER in older adult populations. When comparing the net benefit of two or more interventions for older adults, investigators should consider the following: absolute risk difference, competing risks, life expectancy, the difference between chronologic and physiologic age, the importance of patient preferences, and other potential drivers of variable treatment effects. Investigators should also engage older adults and their caregivers as partners throughout the research process. Their input helps to identify key outcomes of interest and insights about the conduct of the research. As the PCORI continues to support research that addresses the healthcare decisions of the rapidly growing older adult population, it needs to partner with patients and researchers to identify the most important questions to address. J Am Geriatr Soc 67:21-28, 2019.

Update on the Methods of the U.S. Preventive Services Task Force: Linking Intermediate Outcomes and Health Outcomes in Prevention.

The U.S. Preventive Services Task Force (USPSTF) is an independent body of experts who make evidence-based recommendations about clinical preventive services using a transparent and objective process. Developing recommendations on a clinical preventive service requires evidence of its effect on health outcomes. Health outcomes are symptoms, functional levels, and conditions that affect a patient's quantity or quality of life and are measured by assessments of physical or psychologic well-being. Intermediate outcomes are pathologic, physiologic, psychologic, social, or behavioral measures related to a preventive service. Given the frequent lack of evidence on health outcomes, the USPSTF uses evidence on intermediate outcomes when appropriate. The ultimate goal is to determine precisely a consistent relationship between the direction and magnitude of change in an intermediate outcome with a predictable resultant direction and magnitude of change in the health outcomes. The USPSTF reviewed its historical use of intermediate outcomes, reviewed methods of other evidence-based guideline-making bodies, consulted with other experts, and reviewed scientific literature. Most important were the established criteria for causation, tenets of evidence-based medicine, and consistency with its current standards. Studies that follow participants over time following early treatment, stratify patients according to treatment response, and adjust for important confounders can provide useful information about the association between intermediate and health outcomes. However, such studies remain susceptible to residual confounding. The USPSTF will exercise great caution when making a recommendation that depends on the evidence linking intermediate and health outcomes because of inherent evidence limitations.

AHRQ series on complex intervention systematic reviews-paper 3: adapting frameworks to develop protocols.

BACKGROUND: Once a proposed topic has been identified for a systematic review and has undergone a question formulation stage, a protocol must be developed that specifies the scope and research questions in detail and outlines the methodology for conducting the systematic review. RATIONALE: Framework modifications are often needed to accommodate increased complexity. We describe and give examples of adaptations and alternatives to traditional analytic frameworks. DISCUSSION: This article identifies and describes elements of frameworks and how they can be adapted to inform the protocol and conduct of systematic reviews of complex interventions. Modifications may be needed to adapt the population, intervention, comparators, and outcomes normally used in protocol development to successfully describe complex interventions; in some instances, alternative frameworks may be better suited. Possible approaches to analytic frameworks for complex interventions that illustrate causal and associative linkages are outlined, including time elements, which systematic reviews of complex interventions may need to address. The need for and specifics of the accommodations vary with details of a specific systematic review. This in turn helps determine whether traditional frameworks are sufficient, can be refined, or if alternate frameworks must be adopted.

Developing Recommendations for Evidence-Based Clinical Preventive Services for Diverse Populations: Methods of the U.S. Preventive Services Task Force.

The U.S. Preventive Services Task Force (USPSTF) summarizes the principles and considerations that guide development of its recommendations for diverse U.S. populations. It uses these principles through each step in the evidence-based guideline process: developing the research plan, conducting the evidence review, developing the recommendation, and communicating to guideline users. Three recent recommendations provide examples of how the USPSTF has used these principles: the 2015 recommendation on screening for abnormal blood glucose and type 2 diabetes; the 2016 recommendation on screening for breast cancer; and the recommendation on screening for prostate cancer, which is currently in progress. A more comprehensive list of recommendations that includes considerations for specific populations is also provided.

An approach to addressing subpopulation considerations in systematic reviews: the experience of reviewers supporting the U.S. Preventive Services Task Force.

BACKGROUND: Guideline developers and other users of systematic reviews need information about whether a medical or preventive intervention is likely to benefit or harm some patients more (or less) than the average in order to make clinical practice recommendations tailored to these populations. However, guidance is lacking on how to include patient subpopulation considerations into the systematic reviews upon which guidelines are often based. In this article, we describe methods developed to consistently consider the evidence for relevant subpopulations in systematic reviews conducted to support primary care clinical preventive service recommendations made by the U.S. Preventive Services Task Force (USPSTF). PROPOSED APPROACH: Our approach is grounded in our experience conducting systematic reviews for the USPSTF and informed by a review of existing guidance on subgroup analysis and subpopulation issues. We developed and refined our approach based on feedback from the Subpopulation Workgroup of the USPSTF and pilot testing on reviews being conducted for the USPSTF. This paper provides processes and tools for incorporating evidence-based identification of important sources of potential heterogeneity of intervention effects into all phases of systematic reviews. Key components of our proposed approach include targeted literature searches and key informant interviews to identify the most important subpopulations a priori during topic scoping, a framework for assessing the credibility of subgroup analyses reported in studies, and structured investigation of sources of heterogeneity of intervention effects. CONCLUSIONS: Further testing and evaluation are necessary to refine this proposed approach and demonstrate its utility to the producers and users of systematic reviews beyond the context of the USPSTF. Gaps in the evidence on important subpopulations identified by routinely applying this process in systematic reviews will also inform future research needs.

Fit for purpose: perspectives on rapid reviews from end-user interviews.

BACKGROUND: There is increasing demand for rapid reviews and timely evidence synthesis. The goal of this project was to understand end-user perspectives on the utility and limitations of rapid products including evidence inventories, rapid responses, and rapid reviews. METHODS: Interviews were conducted with key informants representing: guideline developers (n = 3), health care providers/health system organizations (n = 3), research funders (n = 1), and payers/health insurers (n = 1). We elicited perspectives on important characteristics of systematic reviews, acceptable methods to streamline reviews, and uses of rapid products. We analyzed content of the interview transcripts and identified themes and subthemes. RESULTS: Key informants identified the following as critical features of evidence reviews: (1) originating from a reliable source (i.e., conducted by experienced reviewers from an established research organization), (2) addressing clinically relevant questions, and (3) trusted relationship between the user and producer. Key informants expressed strong preference for the following review methods and characteristics: use of evidence tables, quality rating of studies, assessments of total evidence quality/strength, and use of summary tables for results and conclusions. Most acceptable trade-offs to increase efficiencies were limiting the literature search (e.g., limiting search dates or language) and performing single screening of citations and full texts for relevance. Key informants perceived rapid products (particularly evidence inventories and rapid responses) as useful interim products to inform downstream investigation (e.g., whether to proceed with a full review or guideline, direction for future research). Most key informants indicated that evidence analysis/synthesis and quality/strength of evidence assessments were important for decision-making. They reported that rapid reviews in particular were useful for guideline development on narrow topics, policy decisions when a quick turn-around is needed, decision-making for practicing clinicians in nuanced clinical settings, and decisions about coverage by payers/health insurers. Rapid reviews may be more relevant within specific clinical settings or health systems; whereas, broad/national guidelines often need a traditional systematic review. CONCLUSIONS: Key informants interviewed in our study indicated that evidence inventories, rapid responses, and rapid reviews have utility in specific decisions and contexts. They indicated that the credibility of the review producer, relevance of key questions, and close working relationship between the end-user and producer are critical for any rapid product. Our findings are limited by the sample size which may have been too small to reach saturation for the themes described.

Primary Care Interventions to Support Breastfeeding: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Although 80% of infants in the United States start breastfeeding, only 22% are exclusively breastfed up to around 6 months as recommended by a number of professional organizations. Objective: To systematically review the evidence on the benefits and harms of breastfeeding interventions to support the US Preventive Services Task Force in updating its 2008 recommendation. Data Sources: MEDLINE, PubMed, Cumulative Index for Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, and PsycINFO for studies published in the English language between January 1, 2008, and September 25, 2015. Studies included in the previous review were re-evaluated for inclusion. Surveillance for new evidence in targeted publications was conducted through January 26, 2016. Study Selection: Review of randomized clinical trials and before-and-after studies with concurrent controls conducted in a developed country that evaluated a primary care-relevant breastfeeding intervention among mothers of full- or near-term infants. Of 211 full-text articles reviewed, 52 studies met inclusion criteria. Thirty-one studies were newly identified, and 21 studies were carried forward from the previous review. Data Extraction and Synthesis: Independent critical appraisal of all provisionally included studies. Data were independently abstracted by one reviewer and confirmed by another. Main Outcomes and Measures: Child and maternal health outcomes, rates and duration of breastfeeding, and harms related to interventions as prespecified before data collection. Results: Fifty-two studies (n = 66 757) in 57 publications were included. Six trials (n = 2219) reported inconsistent effects of the interventions on infant health outcomes; no studies reported maternal health outcomes. Pooled estimates based on random-effects meta-analyses using the DerSimonian and Laird method indicated beneficial associations between individual-level breastfeeding interventions and any breastfeeding for less than 3 months (risk ratio [RR], 1.07 [95% CI, 1.03-1.11]; 26 studies [n = 11 588]), at 3 to less than 6 months (RR, 1.11 [95% CI, 1.04-1.18]; 23 studies [n = 8942]), and for exclusive breastfeeding for less than 3 months (RR, 1.21 [95% CI, 1.11-1.33]; 22 studies [n = 8246]), 3 to less than 6 months (RR, 1.20 [95% CI, 1.05-1.38]; 18 studies [n = 7027]), and at 6 months (RR, 1.16 [95% CI, 1.02-1.32]; 17 studies [n = 7690]). Absolute differences in the rates of any breastfeeding ranged from 14.1% in favor of the control group to 18.4% in favor of the intervention group. There was no significant association between interventions and breastfeeding initiation (RR, 1.00 [95% CI, 0.99-1.02]; 14 studies [n = 9428]). There was limited mixed evidence of an association between system-level interventions and rates of breastfeeding from well-controlled studies as well as for harms related to breastfeeding interventions, including maternal anxiety scores, decreased confidence, and concerns about confidentiality. Conclusions and Relevance: The updated evidence confirms that breastfeeding support interventions are associated with an increase in the rates of any and exclusive breastfeeding. There are limited well-controlled studies examining the effectiveness of system-level policies and practices on rates of breastfeeding or child health and none for maternal health.

Lipid Screening in Childhood and Adolescence for Detection of Multifactorial Dyslipidemia: Evidence Report and Systematic Review for the US Preventive Services Task Force.

IMPORTANCE: Multifactorial dyslipidemia, characterized by elevated total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C), is associated with dyslipidemia and markers of atherosclerosis in young adulthood. Screening for dyslipidemia in childhood could delay or reduce cardiovascular events in adulthood. OBJECTIVE: To systematically review the evidence on benefits and harms of screening adolescents and children for multifactorial dyslipidemia for the US Preventive Services Task Force (USPSTF). DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, and PubMed were searched for studies published between January 1, 2005, and June 2, 2015; studies included in a previous USPSTF evidence report and reference lists of relevant studies and ongoing trials were also searched. Surveillance was conducted through April 9, 2016. STUDY SELECTION: Fair- and good-quality studies in English with participants 0 to 20 years of age. DATA EXTRACTION AND SYNTHESIS: Two investigators independently reviewed abstracts and full-text articles and extracted data into evidence tables. Results were qualitatively summarized. MAIN OUTCOMES AND MEASURES: Outcomes included dyslipidemia (TC≥200 mg/dL or LDL-C≥130 mg/dL) and atherosclerosis in childhood; myocardial infarction and ischemic stroke in adulthood; diagnostic yield (number of confirmed cases per children screened); and harms of screening or treatment. Simulated diagnostic yield was calculated as initial screening yield × positive predictive value from a study with confirmatory testing. RESULTS: Screening of children for multifactorial dyslipidemia has not been evaluated in randomized clinical trials. Based on 1 observational study (n = 6500) and nationally representative prevalence estimates, the simulated diagnostic yield of screening for elevated TC varies between 4.8% and 12.3% (higher in obese children [12.3%] and at the ages when TC naturally peaks-7.2% at age 9-11 years and 7.2% at age 16-19 years). One good-quality randomized clinical trial (n = 663) found a modest effect of intensive dietary counseling for a low-fat, low-cholesterol diet on lipid levels at 1 year in children aged 8 to 10 years with mild to moderate dyslipidemia; mean between-group difference in TC change from baseline was -6.1 mg/dL (95% CI, -9.1 to -3.2 mg/dL; P < .001). Between-group differences dissipated by year 5. The intervention did not adversely affect nutritional status, growth, or development over the 18-year study period. One observational study (n = 9245) found that TC concentration at age 12 to 39 years was not associated with death before age 55 years. CONCLUSIONS AND RELEVANCE: The diagnostic yield of lipid screening varies by age and body mass index. No direct evidence was identified for benefits or harms of childhood screening or treatment on outcomes in adulthood. Intensive dietary interventions may be safe, with modest short-term benefit of uncertain clinical significance.

Lipid Screening in Childhood and Adolescence for Detection of Familial Hypercholesterolemia: Evidence Report and Systematic Review for the US Preventive Services Task Force.

IMPORTANCE: Familial hypercholesterolemia (FH) is characterized by elevated cholesterol concentrations early in life. Untreated FH is associated with premature cardiovascular disease in adulthood. OBJECTIVE: To systematically review the evidence on benefits and harms of screening adolescents and children for heterozygous FH for the US Preventive Services Task Force (USPSTF). DATA SOURCES: MEDLINE, the Cochrane Central Register of Controlled Trials, and PubMed were searched for studies published between January 1, 2005, and June 2, 2015; studies included in a previous USPSTF report were also searched. Surveillance was conducted through April 8, 2016. STUDY SELECTION: Fair- and good-quality studies in English with participants 0 to 20 years of age. DATA EXTRACTION AND SYNTHESIS: Two investigators independently reviewed abstracts and full-text articles and extracted data into evidence tables. Results were qualitatively summarized. MAIN OUTCOMES AND MEASURES: Myocardial infarction and ischemic stroke in adulthood; lipid concentrations and atherosclerosis in childhood; diagnostic yield of screening; any harm of screening or treatment. RESULTS: Based on 2 studies (n = 83,241), the diagnostic yield of universal screening for FH in childhood is 1.3 to 4.8 cases per 1000 screened. There was no eligible evidence on the benefits or harms of FH screening in childhood. Eight placebo trials of statin drugs (n = 1071, 6-104 weeks) found low-density lipoprotein cholesterol (LDL-C) decreases of 20% to 40%; 1 trial (n = 214) showed a 2.01% decrease in carotid intima-media thickness with statins, compared with 1.02% with placebo (P = .02). Three placebo trials of bile acid-sequestering agents (n = 332, 8-52 weeks) showed LDL-C reductions of 10% to 20%. In 1 trial (n = 248), ezetimibe with simvastatin resulted in greater LDL-C reductions compared with simvastatin alone at 33 weeks (mean, -54.0% [SD, 1.4%] vs -38.1% [SD, 1.4%]). One trial of ezetimibe monotherapy (n = 138) showed mean LDL-C decreases of 28% (95% CI, -31% to -25%) from baseline and negligible change with placebo at 12 weeks. Eighteen studies found statins generally well tolerated. One observational study found lower, but still normal, dehydroepiandrosterone sulfate concentrations in statin-treated males with FH at 10-year follow-up. Bile acid-sequestering agents were commonly associated with adverse gastrointestinal symptoms and poor palatability. There was no eligible evidence on the effect of FH treatment on myocardial infarction or stroke in adulthood. CONCLUSIONS AND RELEVANCE: Screening can detect FH in children, and lipid-lowering treatment in childhood can reduce lipid concentrations in the short term, with little evidence of harm. There is no evidence for the effect of screening for FH in childhood on lipid concentrations or cardiovascular outcomes in adulthood, or on the long-term benefits or harms of beginning lipid-lowering treatment in childhood.

Use of Decision Models in the Development of Evidence-Based Clinical Preventive Services Recommendations: Methods of the U.S. Preventive Services Task Force.

The U.S. Preventive Services Task Force (USPSTF) develops evidence-based recommendations about preventive care based on comprehensive systematic reviews of the best available evidence. Decision models provide a complementary, quantitative approach to support the USPSTF as it deliberates about the evidence and develops recommendations for clinical and policy use. This article describes the rationale for using modeling, an approach to selecting topics for modeling, and how modeling may inform recommendations about clinical preventive services. Decision modeling is useful when clinical questions remain about how to target an empirically established clinical preventive service at the individual or program level or when complex determinations of magnitude of net benefit, overall or among important subpopulations, are required. Before deciding whether to use decision modeling, the USPSTF assesses whether the benefits and harms of the preventive service have been established empirically, assesses whether there are key issues about applicability or implementation that modeling could address, and then defines the decision problem and key questions to address through modeling. Decision analyses conducted for the USPSTF are expected to follow best practices for modeling. For chosen topics, the USPSTF assesses the strengths and limitations of the systematically reviewed evidence and the modeling analyses and integrates the results of each to make preventive service recommendations.

Screening for Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

IMPORTANCE: Colorectal cancer (CRC) remains a significant cause of morbidity and mortality in the United States. OBJECTIVE: To systematically review the effectiveness, diagnostic accuracy, and harms of screening for CRC. DATA SOURCES: Searches of MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant studies published from January 1, 2008, through December 31, 2014, with surveillance through February 23, 2016. STUDY SELECTION: English-language studies conducted in asymptomatic populations at general risk of CRC. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently appraised the articles and extracted relevant study data from fair- or good-quality studies. Random-effects meta-analyses were conducted. MAIN OUTCOMES AND MEASURES: Colorectal cancer incidence and mortality, test accuracy in detecting CRC or adenomas, and serious adverse events. RESULTS: Four pragmatic randomized clinical trials (RCTs) evaluating 1-time or 2-time flexible sigmoidoscopy (n = 458,002) were associated with decreased CRC-specific mortality compared with no screening (incidence rate ratio, 0.73; 95% CI, 0.66-0.82). Five RCTs with multiple rounds of biennial screening with guaiac-based fecal occult blood testing (n = 419,966) showed reduced CRC-specific mortality (relative risk [RR], 0.91; 95% CI, 0.84-0.98, at 19.5 years to RR, 0.78; 95% CI, 0.65-0.93, at 30 years). Seven studies of computed tomographic colonography (CTC) with bowel preparation demonstrated per-person sensitivity and specificity to detect adenomas 6 mm and larger comparable with colonoscopy (sensitivity from 73% [95% CI, 58%-84%] to 98% [95% CI, 91%-100%]; specificity from 89% [95% CI, 84%-93%] to 91% [95% CI, 88%-93%]); variability and imprecision may be due to differences in study designs or CTC protocols. Sensitivity of colonoscopy to detect adenomas 6 mm or larger ranged from 75% (95% CI, 63%-84%) to 93% (95% CI, 88%-96%). On the basis of a single stool specimen, the most commonly evaluated families of fecal immunochemical tests (FITs) demonstrated good sensitivity (range, 73%-88%) and specificity (range, 90%-96%). One study (n = 9989) found that FIT plus stool DNA test had better sensitivity in detecting CRC than FIT alone (92%) but lower specificity (84%). Serious adverse events from colonoscopy in asymptomatic persons included perforations (4/10,000 procedures, 95% CI, 2-5 in 10,000) and major bleeds (8/10,000 procedures, 95% CI, 5-14 in 10,000). Computed tomographic colonography may have harms resulting from low-dose ionizing radiation exposure or identification of extracolonic findings. CONCLUSIONS AND RELEVANCE: Colonoscopy, flexible sigmoidoscopy, CTC, and stool tests have differing levels of evidence to support their use, ability to detect cancer and precursor lesions, and risk of serious adverse events in average-risk adults. Although CRC screening has a large body of supporting evidence, additional research is still needed.

Bleeding Risks With Aspirin Use for Primary Prevention in Adults: A Systematic Review for the U.S. Preventive Services Task Force.

BACKGROUND: The balance between potential aspirin-related risks and benefits is critical in primary prevention. PURPOSE: To evaluate the risk for serious bleeding with regular aspirin use in cardiovascular disease (CVD) primary prevention. DATA SOURCES: PubMed, MEDLINE, Cochrane Central Register of Controlled Trials (2010 through 6 January 2015), and relevant references from other reviews. STUDY SELECTION: Randomized, controlled trials; cohort studies; and meta-analyses comparing aspirin with placebo or no treatment to prevent CVD or cancer in adults. DATA EXTRACTION: One investigator abstracted data, another checked for accuracy, and 2 assessed study quality. DATA SYNTHESIS: In CVD primary prevention studies, very-low-dose aspirin use (≤100 mg daily or every other day) increased major gastrointestinal (GI) bleeding risk by 58% (odds ratio [OR], 1.58 [95% CI, 1.29 to 1.95]) and hemorrhagic stroke risk by 27% (OR, 1.27 [CI, 0.96 to 1.68]). Projected excess bleeding events with aspirin depend on baseline assumptions. Estimated excess major bleeding events were 1.39 (CI, 0.70 to 2.28) for GI bleeding and 0.32 (CI, -0.05 to 0.82) for hemorrhagic stroke per 1000 person-years of aspirin exposure using baseline bleeding rates from a community-based observational sample. Such events could be greater among older persons, men, and those with CVD risk factors that also increase bleeding risk. LIMITATIONS: Power to detect effects on hemorrhagic stroke was limited. Harms other than serious bleeding were not examined. CONCLUSION: Consideration of the safety of primary prevention with aspirin requires an individualized assessment of aspirin's effects on bleeding risks and expected benefits because absolute bleeding risk may vary considerably by patient. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Aspirin for the Primary Prevention of Cardiovascular Events: A Systematic Evidence Review for the U.S. Preventive Services Task Force.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in the United States. PURPOSE: To update a systematic review about the benefits of aspirin for the primary prevention of cardiovascular events in adults aged 40 years or older and to evaluate effect modification in subpopulations. DATA SOURCES: MEDLINE, PubMed, Cochrane Central Register of Controlled Trials (January 2008 to January 2015), and Cochrane Database of Systematic Reviews. STUDY SELECTION: Two investigators independently reviewed 3396 abstracts and 65 articles according to prespecified criteria. All included trials evaluated aspirin for the primary prevention of cardiovascular events. DATA EXTRACTION: Two investigators assessed study quality; data were abstracted by 1 reviewer and checked by a second. DATA SYNTHESIS: Two good-quality and 9 fair-quality randomized, controlled trials were identified. In analyses of all doses, aspirin reduced the risk for nonfatal myocardial infarction (MI) (relative risk [RR], 0.78 [95% CI, 0.71 to 0.87]) but not nonfatal stroke; aspirin showed little or no benefit for all-cause or cardiovascular mortality. Benefits began within the first 5 years. Older adults achieved greater relative MI reduction, but no other effect modifications were found in analyzed subpopulations. In trials with aspirin doses of 100 mg or less per day, the reduction in nonfatal MI benefit persisted (absolute risk reduction, 0.15 to 1.43 events per 1000 person-years) and a 14% reduction in nonfatal stroke benefit was noted, but no benefit was found for all-cause mortality (RR, 0.95 [CI, 0.89 to 1.01]) or cardiovascular mortality (RR, 0.97 [CI, 0.85 to 1.10]). LIMITATION: Evidence for aspirin in primary prevention is heterogeneous and limited by rare events and few credible subgroup analyses. CONCLUSION: The beneficial effect of aspirin for the primary prevention of CVD is modest and occurs at doses of 100 mg or less per day. Older adults seem to achieve a greater relative MI benefit. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Aspirin for the Prevention of Cancer Incidence and Mortality: Systematic Evidence Reviews for the U.S. Preventive Services Task Force.

BACKGROUND: Cancer is the second leading cause of death in the United States. PURPOSE: To conduct systematic reviews of aspirin and 1) total cancer mortality and incidence in persons eligible for primary prevention of cardiovascular disease (CVD) and 2) colorectal cancer (CRC) mortality and incidence in persons at average CRC risk. DATA SOURCES: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials through January 2015 and relevant references from other reviews. STUDY SELECTION: Trials comparing oral aspirin versus placebo or no treatment in adults aged 40 years or older were included. Two investigators independently reviewed abstracts and articles against inclusion and quality criteria. DATA EXTRACTION: Data from 20 good- or fair-quality trials were abstracted by one reviewer and checked by another. DATA SYNTHESIS: In CVD primary prevention trials, cancer mortality (relative risk [RR], 0.96 [95% CI, 0.87 to 1.06]) (10 trials; n = 103 787) and incidence (RR, 0.98 [CI, 0.93 to 1.04]) (6 trials; n = 72 926) were similar in aspirin and control groups over 3.6 to 10.1 years. In CVD primary and secondary prevention trials, 20-year CRC mortality was reduced among persons assigned to aspirin therapy (RR, 0.67 [CI, 0.52 to 0.86]) (4 trials; n = 14 033). Aspirin appeared to reduce CRC incidence beginning 10 to 19 years after initiation (RR, 0.60 [CI, 0.47 to 0.76]) (3 trials; n = 47 464). LIMITATIONS: Most data were from clinically and methodologically heterogeneous CVD prevention trials. Outcome assessment and follow-up length varied across studies. Data on non-CRC cancer types and subgroups were limited. CONCLUSION: In CVD primary prevention populations, aspirin's effect on total cancer mortality and incidence was not clearly established. Evidence from CVD primary and secondary prevention studies suggested that aspirin therapy reduces CRC incidence and perhaps mortality approximately 10 years after initiation. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.